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Category: genetics

Genetically modified marmosets as a model for human deafness provide a foundation for future gene therapies

Why are some people unable to hear from birth, even though their inner ear appears intact? One possible cause lies in the so-called OTOF gene. It plays a central role in transmitting sound signals from the hair cells to the auditory nerve. Without this function, acoustic information does not reach the brain.

Researchers from the German Primate Center—Leibniz Institute for Primate Research, the University Medical Center Göttingen, and the Max Planck Institute for Multidisciplinary Sciences have now, for the first time, generated marmosets in which this gene has been knocked out precisely. The animals are healthy and develop normally, but are deaf from birth. This provides the first primate model that realistically replicates key characteristics of human deafness. The results are published in Nature Communications.

Hearing loss is one of the most common congenital sensory disorders in humans. A major cause is a defect in the OTOF gene. This gene ensures that the protein otoferlin is produced in the inner ear. This protein is necessary for sound signals to travel from the hair cells to the auditory nerve. Without it, the ear still functions externally, but the signals do not reach the brain.

Bile acid and steroid signatures tied to extreme longevity

Centenarians often live to 100+ due to a combination of protective genetic factors, which account for up to 50%, and healthy lifestyles, such as plant-forward diets, regular, natural movement and strong social connections. While these “agers” often possess unique immune system signatures, understanding the metabolic signs of healthy aging is not yet fully understood.

In a new study from Boston University Chobanian & Avedisian School of Medicine, researchers have discovered that centenarians have a distinct blood metabolite pattern that is not just an extension of normal aging. In particular, they show uniquely higher levels of certain primary and secondary bile acids and preserved levels of several steroids, patterns that diverge from the typical age trends seen in non-centenarians and that are linked to lower death risk. The study is published in the journal GeroScience.

“Our study points to measurable chemical fingerprints in the blood that are associated with living a very long and healthy life. If we can understand those fingerprints, we may identify biological pathways that could contribute to protecting people from age-related decline,” explains corresponding author Stefano Monti, Ph.D., professor of medicine at the school.

Epigenetic and transcriptomic impacts of ethanol vary by brain region and extent of exposure

New in eNeuro from Periandri et al: Systematically comparing brain markers affected by brief versus long-term exposure to alcohol in mice unveils shared and different mechanisms that may inform alcohol use disorder treatment development.

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Epigenetic and transcriptional mechanisms are key contributors to alcohol use disorder (AUD). However, a better understanding of the specific genes, transcripts, and chromatin marks affected is necessary to inform novel pharmacotherapies. Here, we systematically investigate the genome-wide epigenetic and transcriptomic effects of ethanol across key brain regions relevant to AUD and assess how these outcomes differ between acute and chronic exposure in male C57BL/6J mice. We show that alcohol-derived acetate contributes to histone acetylation in the brain in response to acute or chronic exposure, with a broader and more robust effect following repeated exposure. Further, we find that chromatin and transcriptomic changes elicited by acute or chronic ethanol exposure are predominantly specific to brain region, and observe more robust dysregulation of gene and transcript expression following acute exposure. We show that ethanol-induced transcriptional changes are paradigm-dependent in some brain regions, most strikingly in the ventral hippocampus. Overall, our results systematically illuminate and compare key epigenetic and transcriptomic outcomes linked to acute and chronic ethanol exposure, which will guide the development of future therapeutic interventions.

Significance Statement This is the first study to systematically investigate epigenetic and transcriptomic changes following acute or chronic exposure to alcohol, focusing on key regions previously linked to substance use disorders. We show the molecular impact of alcohol varies among brain regions and in part depends on the extent of alcohol exposure. Our results provide unprecedented detail on how alcohol affects transcriptional regulation in the brain, which in turn will inform the development of needed novel therapeutic interventions for alcohol use disorder.

Retroperitoneal fibrosis

Retroperitoneal fibrosis is a rare immune-mediated disease characterised by a periaortoiliac fibro-inflammatory tissue that often encases neighbouring structures (eg, ureters). Idiopathic retroperitoneal fibrosis can be isolated or part of IgG4-related disease, whereas secondary forms recognise different aetiologies, such as histiocytosis, malignancies, and infections. Idiopathic retroperitoneal fibrosis has a multifactorial origin, with genetic, environmental, and lifestyle factors being main contributors.

Scientists Discover How to Stop Vision Loss Before It Starts

Scientists have identified molecules that can protect the eye’s cone cells from degeneration, a major cause of vision loss. The discovery points to new drug targets—and even uncovers compounds that may be harmful.

Researchers led by Botond Roska at the Institute of Molecular and Clinical Ophthalmology Basel (IOB), along with an international team, have uncovered genetic pathways and chemical compounds that can help protect cone photoreceptors. These cells are damaged in diseases such as age-related macular degeneration, a leading cause of vision loss.

Why cone cells matter for sight.

Study of 6 Million People Could Rewrite How We Understand Mental Health

From the article:

The study also identified specific brain cell types associated with the genetic patterns.

For the schizophrenia bipolar group, the strongest genetic signals appeared in genes active in excitatory neurons. These neurons transmit signals that activate other brain cells and help different parts of the brain communicate.

In contrast, genetic risk tied to internalizing disorders such as depression, anxiety, and PTSD showed stronger links to oligodendrocytes. These cells help nerve signals travel more efficiently through the brain.

“The findings suggest these ‘support cells’ might play an important role in those conditions,” said Verhulst, research assistant professor and an expert in quantitative and statistical genetics.”

A massive genetic analysis of more than 6 million people is revealing new clues about why mental health disorders frequently overlap.

Continue reading “Study of 6 Million People Could Rewrite How We Understand Mental Health” | >

Long-term inflammatory memory driver identified!

The researchers first gave a bout of psoriasis to mice when they were young. They discovered that about 10–15% of the memories that persisted a month later stuck around even to the end of the mouse’s life (~2 years). To see why these long-term memories lingered while their short-term counterparts faded within six months, they analyzed the DNA sequence characteristics within each of the memories by using a deep learning model customized by the third co-first author.

“When we compared the DNA sequences of short and long-term memory domains, they looked very similar in terms of the numbers and kinds of transcription factor binding sites,” says the author. “We realized we needed to develop a new metric that specifically captures memory persistence across time, not just total accessibility at any one point.”

Soto-Ugaldi’s adaptation, called PersistNet, quickly identified a telling trait: The longest lasting memory domains had an unusually high frequency of CpG dinucleotides—short DNA sequences of cytosine followed by guanine, which are known to play a key role in gene regulation. In fact, the model predicted that CpG density hardwires a timer into every memory domain: The more CpG’s, the longer the memory.

When they tested the prediction, that’s exactly what they found. “Looking across all 1,000 memory domains, we discovered that these nucleotide densities alone, and no other DNA sequence pattern, could distinguish how long each memory would linger,” says the author.

Back in the lab, the team discovered that these genetically wired densities enabled a host of epigenetic changes in memory domains, including DNA demethylation (the removal of a methyl group specifically found on CpG dinucleotides); the binding of transcription factors that prefer demethylated states; and the recruitment of a histone variant called H2A.Z, which preferentially seeks out demethylated sites and boosts chromatin accessibility while staving off future re-methylation. Together, these changes stabilized the open chromatin formation and its gene-priming activity. As the authors discovered, this structure could crucially be passed down across cellular generations, essentially keeping the doors open for life. Science Mission sciencenewshighlights.

One of the most puzzling aspects of common chronic inflammatory skin diseases such as psoriasis is how they become chronic. What allows an ongoing condition to stay dormant for months or even years, then seemingly spring back out of nowhere?

Continue reading “Long-term inflammatory memory driver identified!” | >

Mutation map reveals how amylin mutations influence type 2 diabetes

Researchers at the Institute for Bioengineering of Catalonia (IBEC) have produced a mutational map showing how mutations in amylin—a hormone that plays a key role in glucose regulation—affect its tendency to form toxic amyloid aggregates in the pancreas. This process is linked to the development of type 2 diabetes. While it was already known that certain mutations could alter this aggregation capacity, understanding of this process was fragmented and based on isolated studies. The research is published in the journal Nature Communications.

“For the first time, we can systematically map how thousands of mutations modulate amylin aggregation, bringing human genetics closer to molecular mechanisms,” says Benedetta Bolognesi, the principal investigator of the Protein Phase Transitions in Health and Disease group at IBEC, who is also the lead author of the study.

“We have created a map that allows us to anticipate the potential impact of these mutations in the population,” adds Marta Badia, a researcher in the same group and first author of the study. “We are not assessing toxicity, but rather the protein’s intrinsic propensity to form fibers. This is a first step, but an extremely necessary one.”

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